Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
  • C07D311/56—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 without hydrogen atoms in position 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
  • C07D311/64—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with oxygen atoms directly attached in position 8

Definitions

• alkyl means straight-chain or branched saturated hydrocarbon residues. This also applies to alkyl residues that are contained in alkoxy radicals.
• alkyl radicals are methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
• Cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• alkylene and alkenylene radicals which represent group B are 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, 1,3-prop-1-enylene, 1,3-prop-2-enylene, 1,4-but-1-enylene, 1,4-but-2-enylene, 1,4-but-3-enylene, 1,5-pent-1-enylene, 1,5-pent-2-enylene, 1,5-pent-3-enylene and 1,5-pent-4-enylene.
• substituted phenyl radicals which occur as such or in benzyl radicals can, the substituents can be in any positions, at Mono substitution e.g.
• Halogen means, unless otherwise indicated fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
• the compounds of formula I are valuable active pharmaceutical ingredients for Human and veterinary medicine, in particular for the treatment of Cardiac arrhythmia and decreased contractility of the heart. Furthermore, they can be used as intermediates for the production of further Active pharmaceutical ingredients are used.
• hypoglycemic effect For certain benzenesulfonylureas is a hypoglycemic effect described.
• the prototype of such hypoglycemic sulfonylureas is considered the glibenclamide, which is used as a treatment for diabetes mellitus is used therapeutically and in research as a much noticed Tool for researching so-called ATP-sensitive potassium channels.
• glibenclamide In addition to its hypoglycemic effect, glibenclamide also has other effects that have not yet been used therapeutically can, but all of them blockade of these ATP-sensitive potassium channels to be led back. This includes in particular an anti-fibrillator Effect on the heart.
• EP-A-325 964 describes chroman compounds as ⁇ 2 -adrenergic antagonists with action against depression, metabolic disorders, glaucoma, migraines and high blood pressure. However, it does not describe any compounds with substitution by sulfonylurea or sulfonylthiourea groups and does not suggest the compounds according to the invention.
• Chromanylsulfonylureas of the formula I are known per se Methods prepared as described in the literature (for example in the Standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York; and in the above-mentioned patent applications), namely under reaction conditions for the reactions mentioned are known and suitable. You can also from well-known, here but make use of variants not mentioned in more detail.
• the raw materials can, if desired, also be formed in situ in such a way that they are formed from not isolated from the reaction mixture, but immediately reacted further.
• 4-Aminoalkylchromanes are described, for example, in European patent application EP-A-325 964 and US Pat. Nos. 5,140,039 or 5,185,364 or can be prepared by the methods specified therein.
• Suitable substituted amines of the formula XI can be acylated as indicated in Scheme 1 to give the amides of the formula XII and then subjected to halogen sulfonation.
• Suitable acylating agents for amino groups are expediently the alkyl esters, halides (for example chlorides or bromides) or anhydrides of carboxylic acids of the formula R (5) COY.
• R (5) stands for a trihalomethyl radical or a (C 1 -C 4 ) alkyl radical
• R (5) stands for a benzoic acid derivative of the formula ACOY, where A here according to the meaning of this radical mentioned at the beginning for substituted or unsubstituted phenyl stands.
• Y is a leaving group such as halide, (C 1 -C 4 ) alkoxy, trihaloacetate, (C 1 -C 4 ) carboxylate.
• the syntheses of the compounds of formula XII are usually under Addition of a tertiary base such as pyridine or a trialkylamine in Presence or absence of an inert solvent carried out, wherein a catalyst such as dimethylaminopyridine may also be present.
• the reaction can be carried out at temperatures of about 0 ° C. to 160 ° C., preferably from 20 to 150 ° C can be achieved.
• the acyl group of the compounds of the Formula XII can be both a protecting group and, in the case of Benzoic acid derivatives, i.e. if R (5) for A with the meaning explained above of A is part of the compound of formula I.
• ethers such as tetrahydrofuran, dioxane, glycol ethers such as Ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), Ethylene glycol dimethyl ether, diglyme, ketones such as acetone or butanone, nitriles such as acetonitrile, amides such as dimethylformamide (DMF) or N-methylpyrrolidone (NMP), phosphoric acid hexamethyl triamide, sulfoxides such as DMSO, chlorinated Hydrocarbons such as dichloromethane, chloroform, trichlorethylene, 1,2-dichloroethane or carbon tetrachloride, hydrocarbons such as benzene, Toluene, xylenes. Mixtures of these solvents are also suitable among themselves.
• group A represents the rest of the formula with the definition of B, or B stands for a remainder of the formulas
• the acylated amines corresponding to formula XII can be prepared as follows:
• the amine of the formula XI is first converted into an isocyanate or a reactive carbonic acid derivative.
• the conversion of the amine XI into an isocyanate (Scheme 2) can be carried out in a known manner by reacting XI with
• Carbonic acid halides such as phosgene or triphosgene in the presence of tertiary Alkylamines or pyridine and inert solvents.
• inert Solvents are suitable ethers such as tetrahydrofuran, dioxane, Ethylene glycol dimethyl ether, diglyme, ketones such as acetone or butanone, nitriles such as acetonitrile, nitro compounds such as nitromethane, esters such as ethyl acetate, Amides such as dimethylformamide (DMF) or N-methylpyrrolidone (NMP), Phosphoric acid hexamethyl triamide, sulfoxides such as DMSO, sulfones such as sulfolane, Hydrocarbons such as benzene, toluene, xylenes.
• inert Solvents are suitable ethers such as tetrahydrofuran, dioxane,
• carbonic acid esters come into consideration as they look Chloroformic acid alkyl esters and XI and suitable tertiary alkyl amines or have pyridine synthesized. Furthermore, N, N'-carbonyldiimidazole and analogous reactive derivatives are used as isocyanate equivalents (Staab, H.A., Syntheses with Heterocyclic Amides (Azolides), Angewandte Chemie 74 (1962), No. 12, pp. 407-423).
• the isocyanate of the formula XII a or corresponding urethanes can then be used to introduce the second molecular component with a compound of the formula with the meaning of B or a compound of the formula mentioned above in the presence or absence of inert solvents at temperatures of, for example, 100-170 ° C. (Justus Liebigs Ann. Chem. 1956, 598, p. 203) and provide the acylurea derivatives of the formula XIIb corresponding to the formula XII, in which A represents the heterocyclic radicals mentioned at the beginning (Scheme 3).
• the acylated amines of the formulas XII obtained according to Scheme 1 or 2/3 or XIIb can be converted into the sulfonamides of the formula II in a known manner become.
• the sulfonamides of the formula II are known per se Methods prepared and under reaction conditions for the mentioned implementations are known and suitable. You can also from use known per se, but not mentioned here in more detail do. If desired, the syntheses can be in one, two or more Steps.
• acylated amine of formula XII or XIIb by electrophilic reagents in Presence or absence of inert solvents at temperatures of -10 ° C to 120 ° C, preferably from 0 ° C to 100 ° C, in aromatic sulfonic acids or whose derivatives, such as sulfonic acid halides, are converted.
• sulfonic acids the primary Reaction products, they can either be treated directly or by treatment with tertiary amines, such as pyridine or trialkylamines, or with alkali or Alkaline earth metal hydroxides or reagents that contain these basic compounds Form situ, in a known manner by acid halides such as Phosphorus trihalides, phosphorus pentahalides, phosphorus oxychlorides, Thionyl halides, oxalyl halides, converted into sulfonic acid halides become.
• tertiary amines such as pyridine or trialkylamines
• alkali or Alkaline earth metal hydroxides or reagents that contain these basic compounds Form situ
• the sulfonic acid derivatives are converted into sulfonamides in known in the literature, preferably sulfonic acid chlorides are inert Solvents at temperatures from 0 ° C to 100 ° C with aqueous ammonia implemented. You can also sulfonamides according to the literature Process from the acylated amines of the formula prepared according to scheme 1 XII by reactions with alkaline or alkaline earth metal organic reagents in inert solvents and under an inert gas atmosphere at temperatures of -100 ° C to 50 ° C, preferably from -100 ° C to 30 ° C, reaction with Sulfur dioxide and subsequent thermal treatment with Synthesize sulfamic acid.
• the acyl group R (5) CO acts as a protective group for the amino group in the Compound of formula XI, then this can be shown by the Split off sulfonamides of the formula IIa with acids or bases.
• acids or bases By division with aqueous acids or acids in inert solvents associated acid addition salt are formed.
• aqueous acids or acids in inert solvents associated acid addition salt are formed.
• acids or bases By division with aqueous acids or acids in inert solvents associated acid addition salt are formed.
• hydrohalic acids such as hydrochloric acid or hydrobromic acid
• phosphoric acids such as orthophosphoric acid or Polyphosphoric acid or other common acids with which amides can be split.
• the cleavage of the acylated amine of the formula XII with Bases can also be made in aqueous or inert solvents.
• alkali metal or alkaline earth metal hydroxides or alcoholates such as sodium hydroxide, potassium hydroxide, calcium hydroxide, Sodium hydride, sodium methylate, sodium ethanolate, potassium methylate or Potassium ethanolate.
• the compounds of formula I can have one or more chiral centers have. If one or more chiral centers are present, then connections are the Formula I with uniform stereochemistry preferred at these centers. Compounds of formula I with one or more chiral centers can in their production as racemates or, if optically active starting materials used, can also be obtained in optically active form. Assign the Connections to two or more chiral centers, then they can be at the Synthesis are obtained as mixtures of racemates from which the individual Isomers, for example by recrystallization from inert solvents, in can isolate pure form. Racemates obtained can, if desired, after known methods mechanically or chemically in their enantiomers be separated. So from the racemate by reaction with a optically active release agents diastereomers are formed.
• optically active acids such as the R or R, R and S or S, S forms of tartaric acid, dibenzoyltartaric acid, Diacetyltartaric acid, camphorsulfonic acid, mandelic acid, malic acid or Lactic acid.
• the different forms of the diastereomers can in themselves known manner, for example by fractional crystallization, separated and the enantiomers of the formula I can be obtained in a manner known per se from the Diastereomers are released. Enantiomer separations succeed furthermore by chromatography on optically active carrier materials.
• the compounds of the formula I and their physiologically acceptable salts are valuable therapeutic agents which are not only used as antiarrhythmic agents, but also for the treatment and prophylaxis of disorders of the cardiovascular system, heart failure, heart transplants or cerebral vascular diseases in humans or mammals (for example monkeys, dogs, Mice, rats, rabbits, guinea pigs, cats and larger farm animals (e.g. cattle and pigs) are suitable.
• Physiologically acceptable salts of the compounds of the formula I are understood according to Remmington's Pharmaceutical Science, 17th edition, 1985, pages 14-18, for example compounds of the formula X, which can be prepared from non-toxic organic and inorganic bases and chromanylsulfonyl (thio) ureas of the formula I.
• salts in which the cation M 'in the formula X is a sodium, potassium, rubidium, calcium, magnesium, ammonium ion or an ammonium ion with organic radicals, and the acid addition products from compounds of the formula I and basic Amino acids such as lysine or arginine.
• the salts can be obtained in accordance with the customary procedure, for example by reacting the compounds of the formula I with suitable bases, such as, for example, sodium or potassium hydroxide or an amine, in a solvent or diluent.
• the physiologically acceptable salts are furthermore the addition products with non-toxic inorganic and organic acids, which can also be obtained, for example, by combining the components in a suitable solvent or diluent.
• Suitable acids are, for example, sulfuric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, polyphosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, phenylacetic acid, citric acid, gluc
• the compounds of the present invention are particularly valuable Medicines for the treatment of various types of irregular heartbeat Genesis and to prevent the arrhythmic, sudden Cardiac death and can therefore be used as antiarrhythmics.
• Arrhythmic disorders of the heart are supraventricular Rhythm disorders such as atrial tachycardia, atrial flutter or paroxysmal supraventricular arrhythmia, or ventricular Rhythm disorders such as ventricular extrasystoles, but especially life-threatening ventricular tachycardia or the particularly dangerous Ventricular fibrillation. They are particularly suitable for such cases where Arrhythmias are due to constriction of a coronary artery as they are for example with angina pectoris or during an acute heart attack or occur as a chronic consequence of a heart attack. They are therefore special suitable for the prevention of sudden cardiac death in post-infarct patients.
• rhythm disturbances and / or the Sudden, arrhythmic cardiac death play a role, for example heart failure or cardiac hypertrophy as a result of a chronic increased blood pressure.
• the compounds of the present invention are capable of to positively affect decreased heart contractility. This can it is a disease-related decrease in heart contractility, such as heart failure, but also acute cases such as Heart failure from shock. Likewise, with a Heart transplantation the heart's performance after the operation resume faster and more reliably. The same applies to operations on Heart, which is a temporary cessation of cardiac activity require cardioplegic solutions.
• the compounds of formula I according to the invention and their physiological harmless salts can be used to manufacture pharmaceutical preparations be used. You can do this together with at least one fixed or liquid carrier or excipient alone or in combination with others Drugs, e.g. Cardiovascular active drugs such as calcium antagonists or ACE inhibitors, placed in a suitable dosage form become.
• Drugs e.g. Cardiovascular active drugs such as calcium antagonists or ACE inhibitors
• Pharmaceutical preparations and drugs that are effective Amount of one or more compounds of formula I or their physiological contain harmless salts, the use of the compounds for Manufacture of medicinal products and process for their manufacture Medicaments are also the subject of the present invention. This Preparations can be used as medicinal products in human or veterinary medicine be used.
• Organic or inorganic substances are suitable as carriers, which are for the enteral (for example the oral) or parenteral (for example the intravenous) application or for topical applications and with the Compounds of formula I do not react, for example water, vegetable Oils, alcohols such as ethanol, propanediol or benzyl alcohols, polyethylene glycols, Polypropylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin, petroleum jelly.
• compositions such as tablets, coated tablets, Capsules, suppositories, solutions, preferably oily or aqueous solutions, Syrups, juices or drops, and suspensions or emulsions for which topical application ointments, creams, pastes, lotions, gels, sprays, Foams, aerosols, solutions (for example in alcohols, such as ethanol, Isopropanol or 1,2-propanediol or their mixtures with one another or with Water) or powder.
• Other dosage forms include e.g. also implants in Consideration.
• the compounds of formula I can also be lyophilized and the Lyophilisate obtained for example for the production of injection preparations be used.
• the pharmaceutical preparations can auxiliaries such as lubricants, preservatives, stabilizers and / or Wetting agents, emulsifiers, salts (e.g. to influence the osmotic Pressure), buffer substances, color and taste and / or aroma substances contain. If you wish, you can also add one or more Contain active ingredients, for example one or more vitamins.
• the dosages used to treat cardiac arrhythmias with the Compounds of formula I are necessary depend on whether or acute is treated prophylactically and depends on the individual case. Usually you come up with a dose range of at least 0.01, preferably 0.1 mg, in particular 1 mg to at most 100 mg, preferably 10 mg per kg per day if prophylaxis is practiced. Especially a dose range of 1 to 10 mg per kg and day is suitable.
• the dose can be administered in the form of an oral or parenteral single dose or in several, in particular e.g. up to four single doses can be divided.
• parenteral administration can e.g. by injection or infusion.
• a preferred dose range in critical Situations can then be 10 to 100 mg and, for example, as continuous intravenous infusion.
• 4- (5-chloro-2-methoxy-benzamidomethyl) -6-sulfamoyl-7-ethoxychroman is analogous to the starting compound described in Example 1, starting from 4-aminomethyl-7-ethoxychroman and 5-chloro-2-methoxy-benzoic acid chloride, manufactured. The resulting intermediate is then reacted with chlorosulfonic acid and then with ammonia. 4- (5-Chloro-2-methoxybenzamidomethyl) -6-sulfamoyl-7-ethoxychroman is obtained. Melting point: 204-205 ° C.
• 4 - ((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (isopropylaminothiocarbonylaminosulfonyl) -7-methoxychroman is in Based on example 14 starting from 4 - ((3-ethyl-4-methyl-2-oxo-3-pyrrolin-1-carboxamido) methyl) -6-sulfamoyl-7-methoxychroman and Isopropyl isothiocyanate synthesized. Melting point: 153 ° C.
• Example 14 0.5 g of 4 - ((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (methylaminothiocarbonylaminosulfonyl) -7-methoxychroman (Example 14) are dissolved in 10 ml of cold 0.5N sodium hydroxide solution. In the cold (-4 to 0 ° C) 0.5 ml of 37% hydrogen peroxide solution are added and batch 1 Stirred at 0 ° C for one hour. The product is precipitated by adding 2N HCl. The crude product is purified by chromatography on silica gel (eluent: Methylene chloride / glacial acetic acid 9: 1) cleaned. Melting point: 211 ° C.
• 4 - ((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (methylaminocarbonylaminosulfonyl) -7-ethoxychroman is carried out analogously to Example 18 Oxidation of 4 - ((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (methylaminothiocarbonylaminosulfonyl) -7-ethoxychroman With Hydrogen peroxide solution produced. Melting point: 187-188 ° C.
• 4 - ((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (ethylaminocarbonylaminosulfonyl) -7-ethoxychroman is carried out analogously to Example 18 Oxidation of 4 - ((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl) -6- (ethylaminothiocarbonylaminosulfonyl) -7-ethoxychroman With Recovered hydrogen peroxide solution. Melting point: 175 ° C.
• ATP deficiency such as ischemia in the heart muscle cell observed lead to a shortening of the action potential duration. she are considered one of the causes of so-called reentry arrhythmias that affect the can cause sudden cardiac death.
• Standard microelectrode technology is used to measure the action potential.
• guinea pigs of both sexes are killed by hitting the head, the hearts are removed, the papillary muscles are removed and hung up in an organ bath.
• the organ bath is flushed with Ringer's solution (0.9% NaCl, 0.048% KCl, 0.024% CaCl 2 , 0.02% NaHCO 3 , and 0.1% glucose) and gassed with a mixture of 95% oxygen and 5% carbon dioxide at a temperature of 36 ° C .
• the muscle is stimulated via an electrode with rectangular pulses of 1 V and 1 ms duration and a frequency of 2 Hz.
• the action potential is derived and registered by an intracellularly pierced glass microelectrode, which is filled with 3 M KCl solution.
• the substances to be tested are added to the Ringer's solution in a concentration of 2.2 ⁇ 10 -6 mol per liter.
• the action potential is amplified on an oscilloscope with a Hugo Sachs amplifier.
• the duration of the action potential is determined at a degree of repolarization of 95% (APD 95 ).
• Reductions in action potential are achieved by adding a 1 ⁇ M solution of the potassium channel opener Hoe 234 (Rilmakalim) (W. Linz, E. Klaus, U. Albus, RHA Becker, D.
• Test substances were added to the bath solution as stock solutions in propanediol. The values given refer to measurements 30 min after the addition.
• the APD 95 is used as a control in the presence of HOE 234 and in the absence of the test substance.

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